Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents

ABSTRACT

Benzoheterocyclic distamycin derivatives of formula (I) wherein: n is 2, 3 or 4; A is O, S, or NR, wherein R is hydrogen or C 1  -C 4  alkyl; B is CH or N; R 1  is hydrogen or C 1  -C 4  alkyl; T is selected from; (i) formula (II) wherein: p is zero or 1; R 2  and R 3  are selected, each independently, from: hydrogen, C 1  -C 4  alkyl optionally substituted by one or more fluorine atoms, and C 1  -C 4  alkoxy; R 4  is C 1  -C 4  alkyl or C 1  -C 3  haloalkyl; X 1  is a halogen atom; and (ii) formula (III) wherein X 2  is a halogen atom; and pharmaceutically acceptable salts thereof, are described. Such compounds are useful as antineoplastic and antiviral agents. ##STR1##

This application is a 371 of PCT/E97/05986 filed Oct. 23, 1997.

The present invention refers to new alkylating antitumor and antiviralagents related to the known antibiotic distamycin A: ##STR2## whichbelongs to the family of the pyrroleamidine antibiotics and is reportedto interact reversibly and selectively with DNA-AT sequences interferingwith both replication and transcription [Nature, 203, 1064 (1964); FEBSLetters, 7 (1970) 90; Prog.Nucleic Acids Res.Mol.Biol., 15, 285 (1975)].

DE-A-1795539 describes the preparation of distamycin derivatives inwhich the formyl group of distamycin is replaced by hydrogen or by theacid residue of an organic C₁ -C₄ aliphatic acid or ofcyclopentylpropionic acid.

EP-B-246,868 describes distamycin analogues in which the distamycinformyl group is substituted by aromatic, alicyclic or heterocyclicmoieties bearing alkylating groups.

It has now been found that a new class of distamycin derivatives asdefined hereinunder, wherein the distamycin formyl group is substitutedby a benzoheterocyclic ring bearing an alkylating group, shows valuablebiological properties.

Accordingly, the present invention relates to new distamycin derivativesof formula (I) as defined hereinunder, to a process for preparing them,to pharmaceutical compositions containing them and to their use intherapy, particularly as antitumor and antiviral agents.

Therefore, object of the present invention are distamycin derivatives offormula: ##STR3## wherein: n is 2, 3 or 4;

A is O, S or NR, wherein R is hydrogen or C₁ -C₄ alkyl;

B is CH or N;

R₁ is hydrogen or C₁ -C₄ alkyl;

T is selected from: ##STR4## wherein: p is zero or 1; R₂ and R₃ areselected, each independently, from: hydrogen, C₁ -C₄ alkyl optionallysubstituted by one or more fluorine atoms, and C₁ -C₄ alkoxy; R₄ is C₁-C₄ alkyl or C₁ -C₃ haloalkyl; X₁ is a halogen atom; and ##STR5##wherein X₂ is a halogen atom; or pharmaceutically acceptable saltsthereof.

The present invention includes within its scope also all the possibleisomers covered by formula (I) both separately and in admixture, as wellas the metabolites and the pharmaceutically acceptable bio-precursors(otherwise known as pro-drugs) of the compounds of formula (I).

The alkyl and alkoxy groups may have branched or straight chains. A C₁-C₄ alkyl group is preferably methyl, ethyl or propyl, a C₁ -C₄ alkoxygroup is preferably methoxy or ethoxy, while a C₁ -C₃ haloalkyl group ispreferably 2-chloroethyl or 2-bromoethyl. When substituted by one ormore fluorine atoms, a C₁ -C₄ alkyl group is preferably a C₁ -C₄perfluoroalkyl group, e.g. --CF₃. The halogen atoms X₁ and X₂ arepreferably chlorine or bromine. Particularly preferred values of n are 2and 3.

When T is an alkylating moiety of formula (II) according to item (i)above with p equal to 1, the carboxamido group and the amino group onthe phenyl ring are preferably in meta or para position with respect toeach other, while R₂ and R₃ can be in any of the free positions.

Pharmaceutically acceptable salts of the compounds of formula (I) aretheir salts with pharmaceutically acceptable, either inorganic ororganic, acids. Examples of inorganic acids are hydrochloric,hydrobromic, sulfuric and nitric acid; examples of organic acids areacetic, propionic, succinic, malonic, citric, tartaric, methanesulfonicand p-toluenesulfonic acid.

A preferred class of distamycin derivatives according to the presentinvention is the one of formula (I) wherein:

n is 2 or 3;

A is O, S, NH or NCH₃ ;

B is CH or N;

R₁ is hydrogen;

T is a group of formula (II) according to item (i), wherein

X₁ is chlorine or bromine; R₄ is ethyl, 2-chloroethyl or 2-bromoethyl;R₂ and R₃ are, each independently, hydrogen or methyl; p is zero or 1;or

T is a group of formula (III) according to item (ii), wherein X₂ isbromine or chlorine.

Examples of specific compounds according to the present invention,especially in the form of salts, preferably with hydrochloric acid, arethe following:

1)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

2)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

3)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

4)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

5)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminobenzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

6)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

7)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzothiazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

8)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-bromoethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

9)3-[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

10)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

11)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

12)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

13)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

14)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

15)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

16)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

17)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(αchloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

18)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

19)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

20)3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

21)3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

22)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

23)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

24)3-[1-methyl-4[1-methyl-4[1-methyl4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

25)3-[1-methyl-4[1-methyl-4[1-methyl4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

26)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

27)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

28)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzothiazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

29)3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

30)3-[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

31)3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

32)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

33)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

34)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

35)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

36)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

37)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

38)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[-4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine.

Further object of the present invention is a process for preparing thecompounds of formula (I), and the pharmaceutically acceptable saltsthereof, which comprises:

(1)(a) reacting a compound of formula: ##STR6## wherein n is 2, 3 or 4,with a compound of formula: ##STR7## wherein: A is O, S or NR, wherein Ris hydrogen or C₁ -C₄ alkyl;

B is CH or N;

R₁ is hydrogen or C₁ -C₄ alkyl;

T is selected from: ##STR8## wherein: p is zero or 1; R₂ and R₃ areselected, each independently, from: hydrogen, C₁ -C₄ alkyl optionallysubstituted by one or more fluorine atoms, and C₁ -C₄ alkoxy; R₄ is C₁-C₄ alkyl or C₁ -C₃ haloalkyl; X₁ is a halogen atom; and ##STR9##wherein X₂ is a halogen atom;

Y is hydroxy or a leaving group;

to obtain a compound of formula (I) as defined above; or:

(b) reacting a compound of formula: ##STR10## wherein n, A, B, and R₁are defined as above, with a compound of formula: ##STR11## wherein X₁,R₂, R₃, and R₄ are defined as above, and Y₁ is hydroxy or a leavinggroup;

or with a compound of formula: ##STR12## wherein X₂ is as defined above,and Y₂ is hydroxy or a leaving group;

to obtain a compound of formula (I) as defined above, wherein T is agroup of formula (II) according to item (i) with p equal to 1, or agroup of formula (III) according to item (ii); or:

(c) reacting a compound of formula: ##STR13## wherein p, n, A, B, R₁,R₂, and R₃ are defined as above and R₅ is hydrogen or C₁ -C₄ alkyl, withethylene oxide, so obtaining a compound of formula: ##STR14## wherein p,n, A, B, R₁, R₂, and R₃ are defined as above, and R₆ is equal to R₅ whenR₅ is C₁ -C₄ alkyl, or R₆ is equal to --CH₂ CH₂ --OH when R₅ ishydrogen;

and then reacting the compound of formula (IX) with a halogenatingagent, to obtain a compound of formula (I) as defined above, wherein Tis a group of formula (II) according to item (i) with p equal to zero or1; and

(2) if necessary, converting the so obtained compound of formula (I)into a pharmaceutically acceptable salt thereof.

The reaction of a compound of formula (IV) with a compound of formula(V) (process (a)) can be carried out according to known methods, forinstance those described in EP-B-246,868.

The reaction between a compound of formula (IV) and a compound offormula (V) wherein Y is hydroxy, is preferably carried out with a molarratio (IV):(V) of from 1:1 to 1:2, in an organic solvent, such as, e.g.,dimethylsulphoxide, dimethylacetamide, dimethylformamide, ethanol,benzene, or pyridine, in the presence of an organic or inorganic basesuch as, e.g., triethylamine, N,N'-diisopropylethylamine, or sodium orpotassium carbonate or bicarbonate, and a condensing agent such as,e.g., N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide,N,N'-dicyclohexylcarbodiimide, or 1-hydroxybenzotriazole hydrate. Thereaction temperature may vary from about -10° C. to about 100° C., andthe reaction time from about 1 to about 24 hours.

The reaction between a compound of formula (IV) and a compound offormula (V), wherein Y is a leaving group as defined above, may becarried out with a molar ratio (IV) (V) of from about 1:1 to about 1:2,in an organic solvent, such as, e.g., dimethylformamide, dioxane,pyridine, tetrahydrofurane, or mixtures thereof with water, optionallyin the presence of an organic base, e.g. N,N'-diisopropylethylamine,triethylamine, or an inorganic base, e.g. sodium or potassiumbicarbonate, at a temperature of from about 0° C. to about 100° C., andfor a time varying from about 2 hours to about 48 hours.

The compounds of formula (IV) are known compounds, or may be prepared byknown methods from known compounds: see, for instance, Arcamone et al.Gazzetta Chim. Ital. 97, 1097 (1967).

The compounds of formula (V), wherein Y is hydroxy, and T is a group offormula (II) according to item (i) with p equal to 1, or a group offormula (III) according to item (ii), can be prepared by reacting anamino compound of formula: ##STR15## wherein A, B and R₁ are as definedabove, with a carboxylic acid, or a derivative thereof, of formula(VIIa) or (VIIb) as defined above.

The compounds of formula (V), wherein Y is hydroxy, and T is a group offormula (II) according to item (i) with p equal to zero, can be preparedby reacting a compound of formula: ##STR16## wherein A, B, R₁, and R₅are defined as above, with ethylene oxide and then with a halogenatingagent, analogously to what described above for process (c). Beforecarrying out the reaction, the carboxyl group is preferably protectedwith a suitable protecting group according to known techniques.

The compounds of formula (V) wherein Y is a leaving group can beprepared starting from the corresponding acids through well knownreactions.

The carboxylic acids of formulas (VIIa) and (VIIb), or the derivativesthereof, are commercially available products, or may be prepared throughreactions well known in organic chemistry (see e.g. Tetrahedron Letters31 1299 (1990), Anti-cancer Drug Design 9, 511 (1994)), JACS 62 3495(1940), J.Org.Chem. 26 4996-97 (1961), or Synth.Commun. 24 3129-3134(1994)).

The compounds of formulas (X) and (XI) are commercial products, or canbe obtained by known methods (see e.g. J.Am.Chem.Soc. 80, 4621 (1958),Helv.Chim.Acta 31, 75 (1948), Synth.Commun. 21, 959 (1991), Anti-cancerDrug Design 10, 25 (1995), J.Org.Chem. 26, 4996-97 (1961), orSynth.Commun. 24, 3129-3134 (1994)).

The compounds of formula (VI) can be obtained by nitro-group reduction,according to known methods, of compounds of formula: ##STR17## whereinn, A, B and R₁ are as defined above.

The nitro-derivatives of formula (XII) can be obtained, in turn, byreacting a compound of formula (IV) as defined above with a compound offormula: ##STR18## wherein A, B and R₁ are as defined above, and Y₃ ishydroxy or a leaving group. The compounds of formula (XIII) are knowncompounds, or may be obtained by known methods (see, e.g., TetrahedronLetters 31, 1299 (1990), Anti-cancer Drug Design 9, 511 (1994)), JACS62, 3495 (1940), J.Org.Chem. 26, 4996-97 (1963), or Synth.Commun. 24,3129-3134 (1994)).

The reaction according to process (c) can be carried out analogously towhat described in U.S. Pat. No. 4,738,980. The halogenating agent maybe, e.g., an elemental halide, such as chlorine or bromine, or a thionylhalide, such as thionylchloride. The starting compounds of formula(VIII) may be obtained according to know reactions, e.g. bymono-alkylation of the amino-compounds of formula (VI) as defined above,optionally previously condensed with the corresponding amino benzoicacid, or a derivative thereof.

In the above formulas, the groups Y, Y₁, Y₂, and Y₃ are hydroxy orleaving groups selected, for instance, from chloro,2,4,5-trichlorophenoxy, 2,4-dinitro-phenoxy, succinimido-N-oxy,imidazolyl, and the like.

Salification of a compound of formula (I), as well as preparation of afree compound starting from a salt, may be carried out by known standardmethods. Well known procedures such as, e.g., fractional crystallizationor chromatography, may also be followed for separating a mixture ofisomers of formula (I) into the single isomers.

The compounds of formula (I) may be purified by conventional techniquessuch as, e.g., silica gel or alumina column chromatography, and/or byrecrystallization from an organic solvent such as, e.g., a loweraliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, ordimethylformamide.

Pharmacology

The compounds of formula (I) according to the present invention areuseful as antineoplastic and antiviral agents. Particularly, they showcytostatic properties towards tumor cells, so that they can be useful toinhibit growth of various tumors in mammals, including humans, such as,for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma,bladder carcinoma, colon carcinoma, ovary and endometrial tumors. Otherneoplasias in which the compounds of the present invention can findapplication are, for instance, sarcomas, e.g. soft tissue and bonesarcomas, and the hematological malignancies such as, e.g. leukemias.

The in vitro antitumor activity was evaluated by cytotoxicity studiescarried out on murine L₁₂₁₀ leukemia cells. Cells were derived from invivo tumors and established in cell culture. Cells were used until thetenth passage. Cytotoxicity was determined by counting surviving cellsafter 48 hours treatment.

The percentage of cell growth in the treated cultures was compared withthat of controls. IC₅₀ values (concentration inhibiting 50% of thecellular growth in respect to controls) were calculated ondose-response.

The compounds of the invention were tested also in vivo on L₁₂₁₀ murineleukemia and on murine reticulosarcoma M 5076, showing a very goodantitumoral activity, with the following procedure.

L₁₂₁₀ murine leukemia was maintained in vivo by i.v. serialtransplantation. For experiments, 10⁵ cells were injected i.p. in CD2F1female mice, obtained from Charles River Italy. Animals were 8 to 10weeks old at the beginning of the experiments. Compounds wereadministered i.v. at day +1 after tumor cells injections.

M5076 reticulosarcoma was maintained in vivo by i.m. serialtransplantation. For experiments, 5×10⁵ cells were injected i.m. inC57B16 female mice, obtained from Charles River Italy. Animals were 8 to10 weeks old at the beginning of the experiments. Compounds wereadministered i.v. at day 3, 7 and 11 after tumor injection.

Survival time of mice and tumor growth were calculated and activity wasexpressed in terms of T/C % and T.I. %. ##EQU1## T.I.=% inhibition oftumor growth respect to control Tox=number of mice which died fortoxicity.

Tox determination was made when mice died before the control and/ortested significant body weight loss and/or spleen and/or liver sizereduction were observed.

The compounds of the invention show also a remarkable effectiveness ininterfering with the reproductive activity of pathogenic viruses andprotect tissue cells from viral infections. For example, they showactivity against DNA viruses such as, for instance, herpes, e.g. herpessimplex and herpes zoster viruses, virus vaccinia, RNA viruses such as,e.g., Rhinovirus and Adenovirus, and against retroviruses such as, forinstance, sarcoma viruses, e.g., murine sarcoma virus, and leukemiaviruses, e.g. Friend leukemia virus.

For example, effectiveness against herpes, coxsackie and respiratorysyncytial viruses was tested in a fluid medium as follows. Serialtwo-fold dilutions of the compounds from 200 to 1.5 mcg/ml weredistributed in duplicate 0.1 ml/well in 96 well microplates for tissueculture. Cell suspensions (2×10⁵ cells/ml) infected with about 5×10⁻³TClD₅₀ of virus/cell were immediately added 0.1 ml/well.

After 3-5 day incubation at 37° C. in CO₂ 5%, the cell cultures wereevaluated by microscope observation and Minimum Inhibiting Concentration(MIC) was determined, MIC being the minimum concentration whichdetermines a reduction of cytopathic effect in comparison with theinfected controls.

The compounds of the invention can be administered to mammals, includinghumans, through the usual routes, for example, parenterally, e.g. byintravenous injection or infusion, intramuscularly, subcutaneously,topically or orally. The dosage depends on the age, weight andconditions of the patient and on the administration route. For example,a suitable dosage for administration to adult humans may range fromabout 0.1 to about 150-200 mg pro dose 1-4 times a day.

Further object of the present invention are pharmaceutical compositions,which comprise a compound of formula (I) as an active principle, inassociation with one or more pharmaceutically acceptable carrier and/ordiluent.

The pharmaceutical compositions of the present invention are usuallyprepared following conventional methods and are administered in apharmaceutically suitable form. For instance, solutions for intravenousinjection or infusion may contain as a carrier, for example, sterilewater or preferably, they may be in the form of sterile aqueous isotonicsaline solutions.

Suspensions or solutions for intramuscular injections may contain,together with the active compound a pharmaceutically acceptable carrier,e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propyleneglycol, and if desired, a suitable amount of lidocaine hydrochloride.

In the forms for topical application, e.g. creams, lotions or pastes foruse in dermatological treatment, the active ingredient may be mixed withconventional oleaginous or emulsifying excipients.

The solid oral forms, e.g. tablets and capsules, may contain, togetherwith the active compound, diluents, e.g., lactose, dextrose, saccharose,cellulose, corn starch and potato starch; lubricants, e.g. silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; binding agents, e.g. starches, arabic gums, gelatin,methylcellulose, carboxymethyl cellulose, polyvinyl-pyrrolidone;disaggregating agents, e.g. starch, alginic acid, alginates, sodiumstarch glycolate; effervescing mixtures; dyestuffs; sweeteners; wettingagents, for instance, lecithin, polysorbates, laurylsulphates; and, ingeneral, non-toxic and pharmacologically inactive substances used inpharmaceutical formulation. Said pharmaceutical preparation may bemanufactered by known techniques, for example by means of mixing,granulating, tabletting, sugar-coating or film-coating processes.

Further object of the present invention are compounds of formula (I) foruse in a method for treating the human or animal body by therapy.

Furthermore, the present invention provides a method for treating tumorsand viral infections in a patient in need of it, which comprisesadministering to said patient a composition of the invention.

A further object of the present invention is a combined method fortreating cancer or for ameliorating the conditions of mammals, includinghumans, suffering from cancer, said method comprising administering acompound of formula (I), or a pharmaceutically acceptable salt thereof,and an additional antitumor agent, close enough in time and in amountssufficient to produce a therapeutically useful effect.

The present invention also provides products containing a compound offormula (I), or a pharmaceutically acceptable salt thereof, and anadditional antitumour agent as a combined preparation for simultaneous,separate or sequential use in anti-cancer therapy.

The term "antitumor agent" is meant to comprise both a single antitumordrug and "cocktails" i.e. a mixture of such drugs, according to theclinical practice. Examples of antitumor agents that can be formulatedwith a compound of formula (I), or alternatively, can be administered ina combined method of treatment, include doxorubicin, daunomycin,epirubicin, idarubicin, etoposide, fluoro-uracil, melphalan,cyclophosphamide, 4-demethoxy daunorubicin, bleomycin, vinblastin, andmitomycin, or mixtures thereof.

The following examples are given to better illustrate the invention, butdo not limit the scope of the invention itself.

EXAMPLE 13-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride

Step I: The intermediate5-N,N-bis(2-chloroethyl)aminoindole-2-carboxylic acid

To a solution of 200 mg of ethyl 5-aminoindole-2-carboxylate (preparedas reported in J.Am.Chem.Soc. 80, 4621 (1958)) in 10 ml of methanolcooled at -10° C., cold ethylene oxide (2.5 ml) was added. The reactionflask was sealed and allowed to reach room temperature overnight.Methanol and excess of ethylene oxide were removed by evaporation andthe crude residue purified by flash chromatography obtaining 230 mg ofethyl 5-N,N-bis(2-hydroxyethyl)aminoindole-2-carboxylate which wascooled in ice and 2 ml of phosphorus oxychloride were added. Thesolution was heated at 100° C. for one hour, then solvent evaporatedunder vacuum, the residue dissolved in 7 ml of 23% hydrochloric acid andheated at 100° C. for two hours. The solution was cooled at roomtemperature, diluted with 30 ml of water and extracted twice with ethylacetate (2×50 ml). The organic phases were evaporated in vacuo and theresidue purified by flash chromatography using a methylenechloride/methanol mixture, yielding 220 mg of the intermediate.

By analogous procedure and using the opportune starting materials thefollowing products can be obtained:

5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxylic acid;

1-methyl-5-N,N-bis(2-chloroethyl)aminoindole-2-carboxylic acid;

5-N,N-bis(2-chloroethyl)aminobenzothiophene-2-carboxylic acid

5-N,N-bis(2-chloroethyl)aminobenzoimidazole-2-carboxylic acid;

1-methyl-5-N,N-bis(2-chloroethyl)aminobenzoimidazole-2-carboxylic acid;

5-N,N-bis(2-chloroethyl)aminobenzothiazole-2-carboxylic acid;

5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxylicacid;

5-[4-[N-ethyl-N(2-chloroethyl)]aminobenzene-1-carboxamido]indole-2-carboxylicacid;

5-N,N-bis(2-bromoethyl)aminoindole-2-carboxylic acid;

5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxylicacid.

Step II: The Title Compound

A solution of 263 mg of N-deformyldistamycin A dihydrochloride (preparedas reported in J.Med.Chem. 32, 774-778 (1989)) in 5 ml of drydimethylformamide (DMF) was cooled to 5° C. and added with 86 ml ofN,N'-diisopropylethylamine. After 10 min, 175 mg of intermediateobtained from step I and 192 mg ofN-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDCI) were added. Thereaction was stirred at room temperature for 10 hours, then 2Nhydrochloric acid was added up to pH=4. The solvent was removed underreduced pressure and the crude residue purified by flash chromatography(methylene chloride/methanol:8/2) to give 210 mg of the title compoundas a yellow solid.

FAB-MS: m/z 736, (20, [M+H]⁺)

PMR (DMSO-d₆) δ: 11.35 (d, J=1.8 Hz, 1H), 10.29 (s, 1H), 9.96 (s, 1H),9.89 (s, 1H), 8.93 (b.s., 2H), 8.56 (b.s., 2H), 8.18 (t, J=5.6 Hz, 1H),7.30 (m, 2H), 7.10 (d, J=1.8 Hz, 1H), 7.20 (d, J=1.8 Hz, 1H), 7.14 (d,J=1.8 Hz, 1H), 7.04 (d, J=1.8 Hz, 1H) 7.02 (d, J=1.8 Hz, 1H), 6.92 (d,J=1.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 6.84 (dd, J=2.3 Hz and J=9.0 Hz,1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.66 (m, 8H), 3.46 (m,2H), 2.57 (m, 2H)

By analogous procedure and using the opportune starting materials thefollowing products can be obtained:

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 750, (25, [M+H]⁺)

PMR (DMSO-d₆) δ: 10.35 (s, 1H), 9.99 (s, 1H), 9.92 (s, 1H), 8.97 (b.s.,2H), 8.60 (b.s., 2H), 8.22 (t, J=5.5 Hz, 1H), 7.43 (d, J=9.8 Hz, 1H),6.9-7.4 (m, 9H), 3.96 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H),3.72 (m, 8H), 3.50 (m, 2H), 2.61 (m, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 737, (20, [M+H]⁺)

PMR (DMSO-d₆) δ: 10.60 (s, 1H), 9.98 (s, 1H), 9.90 (s, 1H), 8.94 (b.s.,2H) 8.56 (b.s., 2H), 8.19 (t, J=5.6 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H),7.50 (s, 1H), 6.9-7.4 (m, 8H), 3.86 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H),3.75 (m, 8H), 3.50 (m, 2H), 2.61 (m, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminobenzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 753, (60, [M+H]⁺)

PMR (DMSO-d₆) δ: 10.55 (s, 1H), 9.97 (s, 1H), 9.89 (s, 1H), 8.17 (t,J=5.9 Hz, 1H), 8.06 (s, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.29 (d, J=1.7 Hz,1H), 7.23 (d, J=1.7 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.16 (d, J=1.7 Hz,1H), 7.09 (d, J=1.7 Hz, 1H), 7.06 (d, J=1.7 Hz, 1H), 7.06 (dd, J=9.0,2.6 Hz, 1H), 6.95 (d, J=1.7 Hz, 1H), 3.7-3.9 (m, 8H), 3.87 (s, 3H), 3.84(s, 3H), 3.80 (s, 3H), 3.48 (m, 2H), 2.58 (t, J=6.6 Hz, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzothiazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-bromoethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethylaminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride.

EXAMPLE 23-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride

Step I: The intermediate 5-α-bromoacrylamidobenzofurane-2-carboxylicacid

To a solution of 500 mg of commercial α-bromoacrylic acid in 5 ml ofacetonitrile, a solution of 343 mg of N,N-dicyclohexylcarbodiimide in 15ml of acetonitrile was slowly added. After one hour, the solutionobtained after filtration of the precipitate was added to a solution of294 mg of 5-amino-2-benzofuranic acid (prepared as reported inHelv.Chim.Acta 31, 75 (1948)) and 229 mg of sodium bicarbonate in 20 mlof water. The reaction was stirred at room temperature for one hour,then 2N hydrochloric acid was added up to pH=4. The solution wasextracted with ethyl acetate (3×10 ml), dried over sodium sulfate andevaporated to dryness in vacuo and the crude residue purified by flashchromatography with a methylene chloride/methanol mixture to yield 500mg of the intermediate as a pale yellow solid.

By analogous procedure and using the opportune starting materials thefollowing products can be obtained:

5-α-bromoacrylamidobenzothiophene-2-carboxylic acid;

5-α-bromoacrylamidoindole-2-carboxylic acid;

1-methyl-5-α-bromoacrylamidoindole-2-carboxylic acid;

5-α-bromoacrylamidobenzoimidazole-2-carboxylic acid;

1-methyl-5-α-bromoacrylamidobenzoimidazole-2-carboxylic acid;

5-α-bromoacrylamidobenzothiazole-2-carboxylic acid;

5-α-chloroacrylamidoindole-2-carboxylic acid;

1-methyl-5-α-chloroacrylamidoindole-2-carboxylic acid;

5-α-chloroacrylamidobenzoimidazole-2-carboxylic acid.

Step II: The Title Compound

A solution of 263 mg of N-deformyldistamycin A dihydrochloride (preparedas reported in J.Med.Chem. 32, 774-778 (1989)) in 5 ml of dry DMF wascooled to 5° C. and added with 0.086 ml of N,N'-diisopropylethylamine.After 10 min, 180 mg of the intermediate obtained from step I, and 192mg of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDCI) were added.The reaction was stirred at room temperature for 16 hours, then 2Nhydrochloric acid was added up to pH=4. The solvent was evaporated invacuo and the crude residue purified by flash chromatography (methylenechloride/methanol:8/2) to yield a yellow oil which was precipitated frommethanol/diethyl ether obtaining 240 mg of the title compound as a paleyellow solid.

FAB-MS: m/z 746, (25, [M+H]⁺)

U.V. (EtOH 95%) λ_(max) =315.4 , ε=42622

PMR (DMSO-d₆) δ: 10.69 (s, 1H), 10.39 (s, 1H), 10.00 (s, 1H), 9.90 (s,1H), 8.92 (b.s., 2H), 8.52 (b.s., 2H), 8.2 (m, 2H), 7.66 (m, 3H), 7.32(d, J=1.8 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.15(d, J=1.8 Hz, 1H) 7.07 (d, J=1.8 Hz, 1H), 6.96 (d, J=1.8 Hz, 1H), 6.77(d, J=3.1 Hz, 1H), 6.31 (d, J=3.1 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H),3.80 (s, 3H), 3.51 (m, 2H), 2.60 (m, 2H).

By analogous procedure and using the opportune starting materials thefollowing products can be obtained:

3-[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 269, (10, [M+H]⁺)

U.V. (EtOH 95%) λ_(max) =310 , ε=35011

PMR (DMSO-d₆) δ: 10.39 (s, 1H), 10.18 (s, 1H), 9.93 (s, 1H), 8.92 (b.s.,2H), 8.54 (b.s., 2H), 8.19 (t, J=5.7 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H),7.50 (d, J=9 0 Hz, 1H), 7.42 (dd, J=9.0 Hz and J=1.5 Hz, 1H), 7.29 (d,J=1.8 Hz, 1H), 7.16 (s, 1H), 7.15 (d, J=1.8 Hz, 1H) 7.06 (d, J=1.8 Hz,1H), 6.92 (d, J=1.8 Hz, 1H), 6.72 (d, J=3.1 Hz, 1H), 6.25 (d, J=3.1 Hz,1H), 3.97 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.44 (m, 2H), 2.60 (m,2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 744, (100, [M+H]⁺)

U.V. (EtOH 95%) λ_(max) =500, ε=39053

PMR (DMSO-d₆) δ: 11.70 (d, J=1.7 Hz, 1H), 10.42 (s, 1H), 10.15 (s, 1H),9.99 (s, 1H), 9.90 (s, 1H), 8.98 (b.s. , 2H), 8.67 (b.s. , 2H), 8.20 (t,J=5.7 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.36 (m, 2H), 7.26 (d, J=1.8 Hz,1H), 7.24 (s, 1H), 7.22 (d, J=1.8 Hz, 1H), 7.16 (d, J=1.8 Hz, 1H) 7.06(d, J=1.8 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 6.72(d, J=3.0 Hz, 1H), 6.23 (d, J=3.0 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H),3.77 (s, 3H), 3.46 (m, 2H), 2.59 (m, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 760, (100, [M+H]⁺)

PMR (DMSO-d₆) δ: 10.44 (s, 1H), 10.23 (s, 1H), 10.00 (s, 1H), 9.93 (s,1H), 8.97 (b.s., 2H), 8.60 (b.s., 2H), 8 .22 (t, J=5.7 Hz, 1H), 8.05 (d,J=1.8 Hz, 1H), 7.54 (d, J=8.9 Hz, 1H), 7.47 (dd, J=8.9 Hz and J=1.9 Hz,1H), 7.25 (d, J=1.8 Hz, 1H), 7.21 (s, 1H), 7.19 (d, J=1.8 Hz, 1H), 7.12(d, J=1.8 Hz, 1H), 7.07 (d, J=1.8 Hz, 1H), 7.05 (d, J=1.8 Hz, 1H), 6.95(d, J=1.8 Hz, 1H), 6.77 (d, J=3.1 Hz, 1H), 6.29 (d, J=3.1 Hz, 1H), 4.01(s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.50 (m, 2H), 2.61(m, 2H)

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 760, (20, [M+H]⁺)

PMR (DMSO-d₆) δ: 10.71 (s, 1H), 10.48 (s, 1H), 9.99 (s, 1H), 9.90 (s,1H), 8.96 (b.s., 2H), 8.65 (b.s., 2H), 8.32 (d, J=2.1 Hz, 1H), 8.24 (s,1H), 8.19 (t, J=5.6 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.65 (dd, J=2.1 Hzand J=9.0 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.22 (d, J=1.8 Hz, 1H), 7.16(d, J=1.8 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 6.91(d, J=1.8 Hz, 1H), 6.80 (d, J=3.0 Hz, 1H), 6.31 (d, J=3.0 Hz, 1H), 3.84(s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.46 (m, 2H), 2.58 (m, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)benzoimidazole-2-carboxamido]pyrrole-2-carboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride.

EXAMPLE 33-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride

Step I: The intermediate1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxylicacid

To a solution of 495 mg of 4-N,N-bis(2-chloroethyl)aminobenzoic acid(prepared as reported in Example 1, Step I) in 20 ml of benzene, 1 ml ofthionyl chloride was added. The mixture was refluxed for two hours, thesolvent evaporated under vacuum, the crude solid residue dissolved in 15ml of dioxane and added portionwise to a solution of 167 mg of1-methyl-5-aminoindole-2-carboxylic acid (prepared as reported inJ.Am.Chem.Soc. 80, 4621 (1958)) and 239 mg of sodium bicarbonate in 20ml of water.

The mixture was stirred for one hour and then added with 2N hydrochloricacid up to pH=4. The solvent was evaporated in vacuo and the residuepurified by flash chromatography on silica gel with a methylenechloride/methanol mixture, yielding 400 mg of the intermediate.

By analogous procedure and using the opportune starting materials thefollowing products can be obtained:

5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxylic acid;

5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzofurane-2-carboxylic acid;

5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzothiophene-2-carboxylic acid;

5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxylic acid;

1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxylic acid;

5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzothiazole-2-carboxylic acid;

5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxylic acid;

1-methyl-5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxylic acid;

5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxylic acid;

5-[4-[N-ethyl-N-(2-chloroethyl)]aminobenzene-1-carboxamido]indole-2-carboxylic acid;

1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxylic acid;

5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxylic acid;

1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxylic acid.

Step II: The Title Compound

To a solution of 320 mg of intermediate (prepared as reported in Step I)in 10 ml of benzene, 0.5 ml of thionyl chloride were added. The mixturewas refluxed for two hours, the solvent evaporated under vacuum, thecrude solid residue dissolved in 15 ml of dioxane and added portionwiseto a solution of 200 mg of N-deformyldistamycin A dihydrochloride(prepared as reported in J.Med.Chem. 32, 774-778 (1989)), 95 mg ofsodium bicarbonate in 10 ml of water.

The mixture was stirred for one hour and then added of 2N hydrochloricacid up to pH=4. The solvent was evaporated in vacuo and the residuepurified by flash chromatography (methylene chloride/methanol:8/2) toyield 250 mg of the title compound as a pale yellow solid.

FAB-MS: m/z 869, (40, [M+H]⁺)

PMR (DMSO-d₆) δ: 10.39 (s, 1H), 9.98 (s, 1H), 9.91 (s, 1H), 9.88 (s, 1H)8.97 (b.s., 2H), 8.63 (b.s., 2H), 8.20 (t, J=5.6 Hz, 1H), 8.15 (d, J=1.8Hz, 1H), 7.90 (m, 2H), 7.58 (dd, J=9.0 Hz and J=1.8 Hz , 1H), 7.50 (d,J=9.0 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.21 (s,1H), 7.19 (d, J=1.8 Hz, 1H), 7.18 (d, J=1.8 Hz, 1H), 7.12 (d, J=1.8 Hz,1H), 7.07 (d, J=1.8 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 6.84 (m, 2H), 4.01(s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.78 (m, 8H), 3.50(m, 2H), 2.61 (m, 2H).

By analogous procedure and using the opportune starting materials thefollowing products can be obtained:

3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido)propionamidinehydrochloride;3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethylaminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 871, (20, [M+H]⁺)

U.V. (EtOH 95%) λ_(max) =313.8, ε=48830

PMR (DMSO-d₆) δ: 10.70 (s, 1H), 10.11 (s, 1H), 9.99 (s, 1H), 9.90 (s,1H), 9.0 (b.s., 2H), 8.7 (b.s., 2H), 8.45 (d, J=1.7 Hz, 1H), 8.24 (s,1H), 8.20 (t, J=5.7 Hz, 1H), 7.90 (m, 3H), 7.76 (dd, J=9.0 Hz and J=2.1Hz, 1H), 7.30 (d, J=1.7 Hz, 1H), 7.22 (d, J=1.7 Hz, 1H), 7.16 (d, J=1.7Hz, 1H), 7.10 (d, J=1.7 Hz, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.90 (d, J=1.7Hz, 1H), 6.82 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.6-3.9(m, 8H), 3.46 (m, 2H), 2.60 (m, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 855, (8, [M+H]⁺)

U.V. (EtOH 95%) λ_(max) =313, ε=63866

PMR (DMSO-d₆) δ: 10.72 (s, 1H), 10.08 (s, 1H), 10.04 (s, 1H), 9.93 (s,1H), 8.90 (b.s., 4H), 8.28 (d, J=2.6 Hz, 1H), 8.23 (t, J=5.6 Hz, 1H),7.91 (m, 2H), 7.76 (dd, J=9.0 Hz and J=2.1 Hz, 1H), 7.68 (s, 1H), 7.65(d, J=9.0 Hz, 1H), 7.34 (d, J=1.7 Hz, 1H), 7.26 (d, J=1.7 Hz, 1H), 7.19(d, J=1.7 Hz, 1H), 7.16 (d, J=1.7 Hz, 1H), 7.07 (d, J=1.7 Hz, 1H), 6.95(d, J=1.7 Hz, 1H), 6.86 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.81 (s,3H), 3.7-3.9 (m, 8H), 3.50 (m, 2H), 2.62 (m, 2H).

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 856, (100, [M+H]⁺)

PMR (DMSO-d₆) δ: 11.05 (s, 1H), 10.06 (s, 1H), 10.04 (s, 1H), 9.92 (s,1H), 8.96 (b.s., 2H), 8.60 (b.s., 2H), 8.28 (m, 1H), 8.22 (t, J=5.9 Hz,1H), 7.90 (m, 2H), 7.64 (m, 2H), 7.39 (d, J=1.7 Hz, 1H), 7.25 (d, J=1.7Hz, 1H), 7.20 (d, J=1.7 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.07 (d, J=1.7Hz, 1H), 6.95 (d, J=1.7 Hz, 1H), 6.85 (m, 2H), 3.6-3.9 (m, 17H), 3.50(m, 2H), 3.60 (m, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzothiazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride;

3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride.

EXAMPLE 4

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride

Step I: The intermediate3-[1-methyl-4-[1-methyl-4[1-methyl-4[4-nitrobenzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride

To a solution of 156 mg of 4-nitrobenzothiophene-2-carboxylic acid(prepared as reported in Synth.Commun. 21, 959 (1991)) in 10 ml ofbenzene, 0.5 ml of thionyl chloride were added. The mixture was refluxedfor two hours, the solvent evaporated under vacuum, the crude solidresidue dissolved in 15 ml of dioxane and added portionwise to asolution of 200 mg of N-deformyldistamycin A dihydrochloride (preparedas reported in J.Med.Chem. 32,774-778 (1989)), 95 mg of sodiumbicarbonate in 10 ml of water.

The mixture was stirred for one hour and then added of 2N hydrochloricacid up to pH=4. The solvent was evaporated in vacuo and the residuepurified by flash chromatography with a methylene chloride/methanolmixture to yield 220 mg of the title compound as a solid.

By analogous procedure and using the opportune starting materials thefollowing products can be obtained:

3-[1-methyl-4[1-methyl-4[1-methyl-4[4-nitrobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[4-nitroindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride;

3-[1-methyl-4[1-methyl-4[4-nitroindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-4-nitroindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4-nitroindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[4-nitrobenzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride;

3-[1-methyl-4[1-methyl-4[4-nitrobenzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-4-nitrobenzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[4-nitrobenzothiazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride.

Step II: The Title Compound

The derivative (220 mg) obtained from Step I was dissolved in 10 ml ofDMF and reduced over Pd catalyst (10% on charcoal) under reducedpressure (50 psi) in a Parr apparatus. The solution obtained afterfiltration of the catalyst was evaporated in vacuo and the solid residuedissolved in 5 ml of dry DMF, cooled to 5° C. and added with 0.055 ml ofN,N'-diisopropylethylamine. After 10 min, 100 mg of4-N,N-bis(2-chloroethyl)aminobenzoic acid (prepared as reported inExample 1, Step I) and 123 mg ofN-ethyl-N'-(3-dimethylaminopropyl)carbodiimide were added. The solutionwas stirred for 12 hours at room temperature, then 2N hydrochloric acidwas added up to pH=4. The solvent was evaporated and the crude residuepurified by flash chromatography (methylene chloride/methanol:8/2) togive 200 mg of the title compound as a yellow solid.

FAB-MS: m/z 871, (20, [M+H]⁺)

U.V. (EtOH 95%) λ_(max) =313.8, ε=48830

PMR (DMSO-d₆) δ: 10.70 (s, 1H), 10.11 (s, 1H), 9.99 (s, 1H), 9.90 (s,1H), 9.0 (b.s., 2H), 8.7 (b.s., 2H), 8.45 (d, J=1.7 Hz, 1H), 8.24 (s,1H), 8.20 (t, J=5.7 Hz, 1H), 7.90 (m, 3H), 7.76 (dd, J=9.0 Hz and J=2.1Hz, 1H), 7.30 (d, J=1.7 Hz, 1H), 7.22 (d, J=1.7 Hz, 1H), 7.16 (d, J=1.7Hz, 1H), 7.10 (d, J=1.7 Hz, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.90 (d, J=1.7Hz, 1H), 6.82 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.6-3.9(m, 8H), 3.46 (m, 2H), 2.60 (m, 2H).

By analogous procedure and using the opportune starting materials thefollowing products can be obtained:

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 269, (10, [M+H]⁺)

U.V. (EtOH 95%) λ_(max) =310 , ε=35011

PMR (DMSO-d₆) δ: 10.39 (s, 1H), 10.18 (s, 1H), 9.93 (s, 1H), 8.92 (b.s.,2H), 8.54 (b.s., 2H), 8.19 (t, J=5.7 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H),7.50 (d, J=9.0 Hz, 1H), 7.42 (dd, J=9.0 Hz and J=1.5 Hz, 1H), 7.29 (d,J=1.8 Hz, 1H), 7.16 (s, 1H), 7.15 (d, J=1.8 Hz, 1H) 7.06 (d, J=1.8 Hz,1H), 6.92 (d, J=1.8 Hz, 1H), 6.72 (d, J=3.1 Hz, 1H), 6.25 (d, J=3.1 Hz,1H), 3.97 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.44 (m, 2H), 2.60 (m,2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

FAB-MS: m/z 746, (25, [M+H]⁺)

U.V. (EtOH 95%) λ_(max) =315.4, ε=42622

PMR (DMSO-d₆) δ: 10.69 (s, 1H), 10.39 (s, 1H), 10.00 (s, 1H), 9.90 (s,1H), 8.92 (b.s., 2H), 8.52 (b.s., 2H), 8.2 (m, 2H), 7.66 (m, 3h), 7.32(d, J=1.8 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.15(d, J=1.8 Hz, 1H) 7.07 (d, J=1.8 Hz, 1H), 6.96 (d, J=1.8 Hz, 1H), 6.77(d, J=3.1 Hz, 1H), 6.31 (d, J=3.1 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H),3.80 (s, 3H), 3.51 (m, 2H), 2.60 (m, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride

3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamiido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4N-ethyl-n(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N-ethyl-n(2-chloroethyl)aminobenzene-1-carboxamido]benzoimidazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride.

What is claimed is:
 1. A compound which is a benzoheterocyclicdistamycin derivative of formula: ##STR19## wherein: n is 2, 3 or 4;A isNR, wherein R is hydrogen or C₁ -C₄ alkyl; B is CH; R₁ is hydrogen or C₁-C₄ alkyl; T is selected from: ##STR20## wherein: p is zero or 1; R₂ andR₃ are selected, each independently, from: hydrogen, C₁ -C₄ alkyloptionally substituted by one or more fluorine atoms, and C₁ -C₄ alkoxy;R₄ is C₁ -C₄ alkyl or C₁ -C₃ haloalkyl; X₁ is a halogen atom; and##STR21## wherein X₂ is a halogen atom; or a pharmaceutically acceptablesalt thereof.
 2. A compound according to claim 1, wherein:n is 2 or 3; Ais NH or NCH₃ ; B is CH; R₁ is hydrogen; T is a group of formula (II)according to item (i), whereinX₁ is chlorine or bromine; R₄ is ethyl,2-chloroethyl or 2-bromoethyl; R₂ and R₃ are, each independently,hydrogen or methyl; p is zero or 1; or T is a group of formula (III)according to item (ii), wherein X₂ is bromine or chlorine.
 3. A compoundaccording to claim 1, selectedfrom:3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-bromoethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;andthe pharmaceutically acceptable salts thereof.
 4. A pharmaceuticalcomposition which comprises an effective amount of a compound as definedin claim 1 as an active principle, in association with one or morepharmaceutically acceptable carriers and/or diluents.
 5. A method ofinhibiting growth of a tumor or tumors in a mammal by administering acompound of formula (I) of claim 1 to the mammal.
 6. The method of claim5 wherein said tumor or tumors is a carcinoma.
 7. The method of claim 6wherein said carcinoma is selected from mammary carcinoma, lungcarcinoma, bladder carcinoma, colon carcinoma.
 8. The method of claim 5wherein the mammal is a human.
 9. A method of treating a viral infectionby administering a compound of formula (I) of claim
 1. 10. A process forproducing a compound as defined in claim 1, which processcomprises:(1)(a) reacting a compound of formula: ##STR22## wherein n is2, 3 or 4, with a compound of formula: ##STR23## wherein: A is NR,wherein R is hydrogen or C₁ -C₄ alkyl;B is CH; R₁ is hydrogen or C₁ -C₄alkyl; T is selected from: ##STR24## wherein: p is zero or 1; R₂ and R₃are selected, each independently, from: hydrogen, C₁ -C₄ alkyloptionally substituted by one or more fluorine atoms, and C₁ -C₄ alkoxy;R₄ is C₁ -C₄ alkyl or C₁ -C₃ haloalkyl; X₁ is a halogen atom; and##STR25## wherein X₂ is a halogen atom; Y is hydroxy or a leaving group;to obtain a compound of formula (I) as defined above; or: (b) reacting acompound of formula: ##STR26## wherein n, A, B, and R₁ are defined asabove, with a compound of formula: ##STR27## wherein X₁, R₂, R₃, and R₄are defined as above, and Y₁ is hydroxy or a leaving group; or with acompound of formula: ##STR28## wherein X₂ is as defined above, and Y₂ ishydroxy or a leaving group; to obtain a compound of formula (I) asdefined above, wherein T is a group of formula (II) according to item(i) with p equal to 1, or a group of formula (III) according to item(ii); or: (c) reacting a compound of formula: ##STR29## wherein p, n, A,B, R₁, R₂, and R₃ are defined as above, and R₅ is hydrogen or C₁ -C₄alkyl, with ethylene oxide, so obtaining a compound of formula:##STR30## wherein p, n, A, B, R₁, R₂, and R₃ are defined as above, andR₆ is equal to R₅ when R₅ is C₁ -C₄ alkyl, or R₆ is equal to --CH₂ CH₂--OH when R₅ is hydrogen; and then reacting the compound of formula (IX)with a halogenating agent, to obtain a compound of formula (I) asdefined above, wherein T is a group of formula (II) according to item(i) with p equal to zero or 1; and (2) if necessary, converting the soobtained compound of formula (I) into a pharmaceutically acceptable saltthereof.